This project concerns the new lymphotropic human herpesviruses 6 (HHV-6, HHV-7 and HHV-8. The overall goal of these studies has been to determine virus involvement in human disease(s). The results of these studies during the past year can be summarized as follows: (i) HHV-6 and HHV-8. Characterization of multiple virus isolates have revealed that the herpesviruses previously designated as HHV-6 fall into two distinct categories. These viruses differed in restriction enzyme pattern of viral DNA, antigenically and epidemiologically. As per these studies, and confirmed by others, these viruses will be classified as Exanthem Subitum Virus (ESV), prototyped by the HHV-6 Z29 strain, and HHV-8, prototyped by the U1102, or by the GS strains. (ii) Disease association of ESV or HHV-6. In addition to viruses from ES patients, we have also analyzed viruses from patients with fatal encephalitis and fatal fulminant hepatitis. All of these viruses were similar to ESV strain Z29. They were distinct from the U1102 strain, as well as from HHV-7 DNA. (iii) Virus reactivation from latency: Analyses of viruses from 8 renal transplant patients and 10 bone marrow transplant patients revealed similarity to the Z29 virus, except minor strain variations in the terminal repeat sequences. In one case of renal transplant the reactivated virus originated from the donor kidneys, in as much as identical viruses were derived from two transplanted kidneys from the same donor. In ES patients, virus can only be recovered during 3-4 days of the acute (high fever) phase, in BMT patients virus could be repeatedly isolated for lengthy time, revealing long term viremia. We conclude that ESV (rather than HHV-8), can be associated with morbidity and mortality in immunocompromised patients. Further studies are designed with additional clinical centers, in the USA, Japan and Israel, to extend these conclusions, as well as to allow early detection of reactivated virus, for more timely therapy with potent anti-viral drugs which are too toxic for lengthy therapy.